The strength behavior of human trabecular bone is a critical component in the etiology of age-related osteoporotic fractures. Most hip fractures occur from falls, during which complex multi-directional ("multiaxial") stresses develop. A multiaxial failure criterion is necessary to determine whether or not the bone will fail under such circumstances. We have investigated so far in this project the multiaxial failure properties of high-density trabecular bone and have developed the first ever three-dimensional, complete multiaxial failure criterion. Our goal now is to extend that work to cover trabecular bone of any density. This is important for hip fractures since low density bone exists in many parts of the proximal femur. Other sites of interest include the proximal tibia, with particular relevance to loosening of total knee implants. It has also recently become clear that DXA, the clinical standard for bone strength assessment, has substantial limitations in its ability to predict fracture and monitor drug therapies. Bone turnover has come under intense scrutiny as a potential replacement for bone mass as a predictor of fracture and assessor of therapy, but the biomechanical mechanisms by which bone turnover might affect bone strength are poorly understood. Our second goal in this project is to understand the mechanisms of trabecular multiaxial failure and from this explain the biomechanical link between bone turnover and bone strength. We are proposing that bone turnover affects the remodeling space and that the resulting changes in the distribution of thickness within trabeculae - reflecting changes in resorption cavity geometry and number - should be manifested as changes in the apparent failure (yield) strain and/or density-strength relation of the trabecular bone, an effect that should be accentuated under multiaxial shear-type loading. This is because there is an interaction between the strain amplification effect associated with resorption cavities and the multiaxial shear-type loading conditions that promote excessive bending of individual trabeculae. A series of cadaver studies are planned to address our first goal, and a Series of animal studies using canine and ovine models are planned for the second goal, in which bone turnover is either elevated (by OVX) or depressed (by alendronate treatment). This project should provide substantial insight into the roles of trabecular bone strength and bone quality on osteoporotic fracture risk and treatment and other orthopedic applications.